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Phosphine (PH3), a widely used pesticide, was found in our recent study to induce oxidative damage in the brain, liver and lung of rats. We also observed that melatonin significantly blocked this action. The present study focused on brain and the magnitude and mechanism of protection of PH3-induced oxidative damage by melatonin in vitro and in vivo. PH3 in whole brain homogenate (3 mg protein/mL Tris–HCl pH 7.4 buffer) induced increasing lipid peroxidation [as malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA)] dependent on concentration (0.25–2 mM) and time (30–150 min), reaching a maximum level of 2.9-fold at 90 min after PH3 at 1 mM. Elevation of MDA + 4-HDA levels by PH3 at 1 mM was also observed in homogenates of cerebral cortex, cerebellum, hippocampus and hypothalamus examined individually. Melatonin at 0.1–2 mM progressively inhibited PH3-induced lipid peroxidation in brain and regions thereof. Additionally, PH3 induced brain DNA oxidation in vitro and in vivo determined as 8-hydroxyguanosine (8-OH-dG). Melatonin at 1 mM significantly suppressed PH3-induced brain DNA oxidation in vitro. PH3 at 4 mg/kg i.p. significantly elevated 8-OH-dG in frontal cortex and melatonin prevented it. PH3 in vivo marginally lowered brain glutathione peroxidase activity and melatonin restored it completely. In contrast, PH3 and melatonin both stimulated superoxide dismutase production. Brain glutathione (GSH) levels in PH3-treated rats were significantly reduced at 30 min and recovered gradually. It is concluded that melatonin, probably because of its free radical scavenging ability, confers marked protection against PH3-induced oxidative toxicity in brain.